Anandamide Is A Natural Neurotransmitter

[EDDIEKIRK]

Anandamide

Cannabis / Marijuana: THC / Anandamide

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Anandamide is a natural neurotransmitter found in the brain that binds to the same neuroreceptors as do cannabinoids. [1] [2] Current research suggests that cannabinoids are very similar to anandamide, which regulates mood, memory, pain, movement, and appetite. [3] Although these recent findings are not thoroughly understood, it is clear that cannabis affects the brain in ways completely dissimilar to other drugs, in accordance with natural neurochemical pathways.



The 1988 discovery of the CB1 receptor, found abundant in the brain, and the 1992 discovery of the CB2 receptor found throughout the body, clearly distinguish cannabinoid compounds from other substances. [4] Cannabinoids bind to anandamide receptors in the frontal lobes of the brain, according o research published by the American Association for the Advancement of Science. [5]



Anadamide is thoguht to be key to the anti-emetic (hunger-inducing) properties of cananbis. Recent studies indicate:



Anandamide induces overeating in rats through a CB1 recptor mediated mechanism. Cannabinoid agonists inhibit the activation of 5-HT3 receptors, a possible mechanism of their anti-emetic effect. Cannabinoid agonists inhibit gastrointestinal motility and gastric emptying in rats. In a recent double-blind study in healthy individuals, an oral dose of delta-9-THC of 10mg/m2 caused a significant delay in gastric emptying compared to placebo. In addition, CB agonists inhibited pentabastrin-induced gastic acid secretion in the rat, presumably by a CB receptor dependent process.[6]



[1] Devane, et al. Science, Vol. 258, pp. 1946-1949, 1992



[2] Axelrod, Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Laboratory of Cell Biology, National Institute of Mental Health, Bethesda MD, 1997



[3] Fackelman, Marijuana and the brain: scientists discover the brains own THC. Science News, Vol. 143, No. 6, p. 88, February 6, 1998



[4] Finn, Cannabinoid Investigations Entering The Mainstream. The Scientist, Vol. 12, No. 3, pp. 1-8, February 2, 1998



[5] Beltramo and Piomelli, Functional role of high-affinity anandamide transport, as revealed by selective inhibition, Science, Vol. 277, No. 5329, p. 1094(4), August 22, 1997



[6] Grotenhermen, Russo. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. New York: The Hawthorn Integrative Healing Press, 2002, Grotenhermen, Effects of Cannabis and the Cannabinoids. Chapter 5, p. 61-62

<strong>Cannabis: Professor Raphael Mechoulam - Discovery of THC in 1964, Anandamide in 1992</strong>

Dr.'s Mechoulam and Schuel on Anandamides

Ron Bain, Boulder Weekly, January 30 - February 6, 2003





You've heard of a "natural high?" Well, it turns out we're all a little bit high all the time, whether or not we smoke dope. In fact, the pleasures derived from marijuana, sex and chocolate are all tied together. by similar chemical reactions in our brains. Right now, there's a naturally occurring molecule in your brain and body that's chemically similar to THC, or delta-9 tetrahydrocannabinol, the stuff in marijuana that gets users high.



The scientists who discovered this natural THC-like body chemical in 1992, most notably Raphael Mechoulam of the Hebrew University of Jerusalem, named it "anandamide" after the Sanskrit word for ecstasy, "ananda". THC molecules can plug into the brain's receptors for anandamides quite easily, he found, but THC lasts longer than anandamides, overwhelming the brain's pleasure sites and causing, at least in novice users, feelings of giddiness and ecstasy.



For almost 30 years, Jewish researchers have dominated the world's research into marijuana and why it produces a "high" when smoked. Recently, Dr. Mechoulam and his counterpart at the University of Buffalo, Herbert Schuel, explained to Boulder Weekly how and why most people are high most of the time.



Mechoulam's and Schuel's ongoing research shows that anandamides appear to be involved in regulating and balancing the body's biochemical systems, influencing or controlling the reproductive, sleep, fight-or-flight and appetite cycles.



"It's a quirk of nature that THC works on our receptors," Mechoulam remarked. "We were lucky to be the only group in the world working on this chemical."



All mammals, fish, birds and reptiles seem to have anandamide-based regulatory systems; it's even found in cacao nuts, from which chocolate is made.



"It is found in substantial quantities in chocolate, and may account for the feelings of pleasure that come from chocolate," Schuel said. Other researchers have found that chocolate seems to prolong the marijuana high, as pot users have long claimed.



Street mythology about marijuana has always held that the drug makes girls easier to seduce, that it makes guys impotent or sterile, that it induces drowsiness, and that it prolongs life by easing cumulative stress. Turns out that these two specialized geniuses, Mechoulam and Schuel, no longer view the above as mythology.



Experiments with rats, Schuel explains, show that marijuana causes some "enhancement of sexual activities," at least for the female rats "who appear much more eager than the males." Tests of heavy pot-smoking human males show lowered sperm counts to the point that marijuana could be considered an effective contraceptive, Schuel said, although "it's not a cut-and-dried thing. Sometimes when both smoke, they have babies."



One of Schuel's studies with sea urchins reveals that anandamides inhibit the process of sperm penetrating and entering the egg cell. When anandamides or THC are present, the sea urchin sperm, which actually has anandamide receptor sites on its surface, cannot break through the egg's tough protein coat.



Many people consider marijuana to be a virtual panacea, good for the prevention and treatment of glaucoma and as a digestive aid, or as a treatment for asthma, nausea, insomnia, constipation, menstrual pain, headaches, hangovers, hiccups, eating disorders and lack of appetite.



Schuel agrees that, with the discovery of anandamides, "there's an enormous potential for new medicines and home remedies. There are medicinal aspects plus the psychogenic effects." Cannabis-based medicines were common in the 19th century and may become so again in the 21st century, the two scientists speculate.



Already, European researchers are testing an anandamide-based stroke treatment that, if used quickly enough, seems to protect and cushion the brain from the worst effects of stroke, Mechoulam said.

History of THC Research

In the early 1960s, Dr. Mechoulam was fresh from post-doctoral studies at the Rockefeller Institute in New York and working at the Weizmann Institute in Rehovot, Israel. He was looking for a unique field of research in which to work and make his scientific name.



"I decided to initiate... a re-examination of the chemistry of hashish," Mechoulam wrote in a 1998 edition of the International Cannabinoid Research Society newsletter. Mechoulam's preliminary research showed that ancient Assyrians used cannabis for mind-expanding and medicinal purposes 4,500 years ago. "Apparently nobody was working on this plant resin, although from a careful perusal of the literature it was quite obvious that, in spite of several claims to the contrary, the active constituent had not been isolated in a pure form and its structure was unknown," he wrote.



Mechoulam persuaded an administrator at the Weizmann Institute to contact Israel's top law enforcement commander "and ask for a few kilograms of hashish," he wrote.



"Within a week I went to police headquarters and signed a receipt, 'free of charge,' for five kilograms of hashish... still packed in their original cotton bags, with the trademarks of the Lebanese suppliers."



Mechoulam thought he had fulfilled all procedural requirements to legally obtain the illicit substance, but later he found out that only the Israeli Ministry of Health could legally dispense "narcotics" and that he had technically broken the law. But he never spent any time in jail and he got to keep his hash stash, Mechoulam explains.



In 1964, Mechoulam and a fellow researcher, Prof. Yehiel Gaoni, isolated THC for the first time. Mechoulam applied to the U.S. National Institute of Health (NIH) for a research grant, and was turned down flatly. "The drug was only used by South American natives and was unknown in the United States, I was told."



But mid-'60s pot politics turned things around. "A U.S. senator had asked NIH whether they knew anything about marijuana, as his son had been caught smoking it," Mechoulam wrote. "The senator wanted to know whether his son had permanently damaged his brain."



Dr. Dani Efron, at that time the head of pharmacology for NIH, contacted Mechoulam immediately. "In order to not look out of touch, they asked for my help. We supplied them with 10 grams of pure delta-9 THC, the entire world supply, and we got a grant," Mechoulam wrote. "Much of the early research on THC in the U.S. was done on our material, although Dr. Efron kept his source of supply a secret."



Dr. Mechoulam has held an NIH grant ever since. In the late 1960s, he went on to synthesize most of the other cannabinoids in marijuana, finding that delta-9 THC is the only one that showed measurable laboratory effects on rhesus monkeys.



In a 1970 article in Science magazine, Mechoulam speculated that the human body metabolized THC into another chemical that acted on the molecular level to produce the drug's high. Later he found this metabolized substance in mammalian urine, leading to today's urinalysis industry... "and we had neglected to patent it!" he added.



In 1988, an American research group that included Bill Devane announced they had found evidence of a cannabinoid receptor in the mammalian brain. Devane joined Mechoulam in Israel to further research this question: Did our brains evolve to receive marijuana?



"We assumed that such a receptor does not exist for the sake of a plant compound," they concluded.



Other drugs, like opium, had been found to bind at the molecular level to brain receptor sites intended for endorphins, the body's natural pain reliever. Mechoulam and Devane decided to look for the natural version of THC, and in 1992 they announced finding a fatty molecule that bound naturally to the cannabinoid receptor site.



"Now, there have been about 12,000 papers published on it," Mechoulam adds proudly.

How Anandamides Work

Anandamides are produced by our brains and bodies to achieve a sort of yin-yang biochemical balance, and do not produce the extreme "high" of marijuana, Mechoulam says.



"They're completely different, from a chemical point of view, from THC," he said. "But they combine in the receptor sites the same way." Anandamides are quickly broken down by the body after they have served their intended purpose, and do not last as long as THC metabolites, which remain in the body for weeks.



"The body, the way I see it, is made of compounds which enhance (biochemical) reactions and compounds which reduce reactions," Mechoulam says. "Anandamide is basically a compound that reduces activity; for example, it reduces the formation of many neurotransmitters that are stimulatory."



Anandamides play a survival role for young mammals, their instinctive suckling behavior seems integrally tied to the presence of anandamides. "If we block the system (from receiving anandamides), there is no suckling," Mechoulam explains.



Scientists today use genetic engineering to create special strains of mice that have no anandamide receptors. "These mice are called 'knock-out' mice... and they survive pretty well," Mechoulam said, but he explained that knock-out mice die at a younger age than their anandamide-receiving counterparts and don't reproduce as well.



What would happen if a human were born without the ability to produce or receive anandamides? "I don't think he or she would be born. I don't think they could survive. It would probably be a very difficult life," Mechoulam remarked.



But it fits the logic of earlier research into the brain chemical dopamine to assume that there are humans who produce too much or too little anandamide, Mechoulam explained. "There are people with lots of dopamine that are schizophrenics and others who don't have enough dopamine.



"Lack of anandamide levels can cause spontaneous abortions" in mammals, Mechoulam said. "And it makes sense that disease would shut down the anandamide system."



But testing a human to see if their anandamide levels are correct would require a painful spinal tap to find the specific enzyme produced by the body' s breakdown of anandamides, which is why today's research remains confined to rats, mice and sea urchins.



"We can't do that painful procedure (to humans) just for research," Mechoulam said.



Across the world, in differing cultures with wildly varying socioeconomic structures, a consistent 10 percent of the population smokes marijuana, studies have shown. Could these be people born with low levels of natural anandamides?



Schuel thinks questions like this will be answered soon, now that countries like Canada and Holland are allowing recreational use of marijuana while anandamides research continues in Israel and Ameica. Here, though, "there's a big disconnect between the public policy world and the science of biochemistry," he said, which will prevent America from legalizing marijuana any time soon.



But there are already websites selling anandamides and a legal snythetic analog of THC that, Schuel estimates, is 100 to 1,000 times stronger than marijuana.



The Israeli Connection



Schuel says that the major reason that research into THC and anandamides is based primarily in Israel, rather than some drug Mecca like Holland or Canada. is that Dr. Mechoulam chooses to live and work there. "Raphael is the big mover. I'm just a little fish in the pond," he said, complimenting the elder Mechoulam, who's 72.



"There are quite a few people and hundreds of groups working on cannabinoids all over the world now," Mechoulam says, diverting all reverence away from himself. "The world is not just made of small countries anymore. It doesn't matter if my fellow researchers are in Canada, France, Spain, NIH or California, we have these frequent contacts. I am currently refereeing several papers that are up for publication."



Schuel thinks the reason it was Jews who broke ground in marijuana research dates back to World War II and has nothing to do with drugs. "Hitler drove all the Jewish physicists out and they came to America and built the bomb," he said, pointing out the tradition of Jewish intellectual inquiry.



"Studying for study's sake is a glorious endeavor," Schuel said, noting that today people from an infinite variety of ethnicities work in the cannabinoids research field all over the world. Compared to their percentages in the general population, Jews are more often drawn to careers in science, academic research or writing than other demographic groups, he noted, so it was only natural that Jewish researchers were first drawn to the esoteric field of marijuana research.



In the January 2003 issue of High Times magazine, writer Chris Bennett claims that ancient Hebrew royalty and religious leaders used anointing oil containing a large amount of marijuana extracts. Bennett, who referenced his article heavily with scriptural and historical citations, goes on to claim that Jesus might have been called Christ because he was anointed with this oil, called "kaneh-bosem," which was reserved for kings.



"Anointing was common among the kings of Israel. It was the sign and symbol of royalty. These kings led their people with the benefits of insights achieved through using the holy anointing oil to become 'possessed with the spirit of the Lord,'" wrote Bennett.



"The ministry of Jesus marked the return of the Jewish Messiah-kings, and thus the re-emergence of the holy oil. Jesus was called the Christ because he violated the Old Testament taboo on the cannabis oil and distributed it freely for initiation rites and to heal the sick and wounded," Bennett.s article continues.



Maybe the claims of Rastafarians.who say that marijuana is a sacrament, that it allows them to be closer to God and that they are one of the lost tribes of Israel, are not too far from the literal truth.



Even Judges Are High



Everyone alive, including parents, politicians, judges, police and jailers, is on a natural anandamide high every day. except perhaps for those who lack certain genes to produce or receive the natural THC-like chemical. Thanks to Mechoulam and Schuel, someday soon there will be cannabinoid-based or anandamide-based medical treatments for those who can't sleep, who have no appetite, who develop strokes or heart conditions, who suffer asthma or glaucoma, who are too restless or anxious, or who suffer any number of other maladies.



When that day comes, perhaps a memorial will go up for every person who suffered or died in prison for smoking or selling an innocent, medicinal herb and to those who devoted their lifetimes to expand the human race's knowledge of marijuana, cannabinoids and anandamides.



Note: Getting stoned is just a matter of degree. Our brains give us all a marijuana-like high every day, like it or not.



source: http://cannabismd.or...anandamides.php

Anandamide Work As Antidepressant

• Boosting the amounts of a marijuana-like brain transmitter called anandamide produces antidepressant effects in test rats, according to American and Italian researchers.
  
  The researchers, led by Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at the University of California, Irvine, used a drug they created, called URB597, which blocks anandamide degradation in the brain, thereby increasing the levels of this chemical.
  
  These findings raise the hope that the mood-elevating properties of marijuana can be harnessed to treat depression, Piomelli said. Marijuana itself has shown no clinical use for depression. However, specific drugs that amplify the actions of natural marijuana-like transmitters in the brain are showing great promise.
  
  The researchers administered URB597 to chronically-stressed rats that demonstrated behaviors similar to those seen in depressed human patients. The stressed rats treated with the drug, after five weeks of treatment, were behaving similarly to a comparison group of unstressed animals.
  
  URB597 works by inhibiting an enzyme in the body FAAH that breaks down anandamide. Anandamide, dubbed as the bliss molecule for its similarities to the active ingredient in marijuana is a neurotransmitter that is part of the brains endocannabinoid system. In studies by Piomelli and others, anandamide has been shown to play analgesic, anti-anxiety, and antidepressant roles besides being involved in the regulation of feeding and obesity. Inhibiting FAAH activity boosts the effects of anandamide without producing the high seen with marijuana.
  
  Piomelli and colleagues at the Universities of Urbino and Parma in Italy created URB597.
  The study appears in an issue of Biological Psychiatry.
  
  Reference:
  University of California
  
  

Anandamide Written by Mario D. Aceto Thursday, 06 November 2008 17:54 0022-3565/98/2872-0598$03.00/0



THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 287, No. 2 Copyright 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 287:598605, 1998



Anandamide, an Endogenous Cannabinoid, Has a Very Low Physical Dependence Potential1



MARIO D. ACETO, SUSAN M. SCATES, RAJ K. RAZDAN and BILLY R. MARTIN



Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University (M.D.A., S.M.S., B.R.M.), Richmond, Virginia and Organix, Inc. (R.K.R.), Woburn, Massachusetts



Accepted for publication June 22, 1998 This paper is available online at http://www.jpet.org



ABSTRACT



Using N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a cannabinoid antagonist, several investigators (deFonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995) demonstrated physical dependence on THC [O9-tetrahydrocannabinol]. This demonstration prompted us to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100,



200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2-methylarachidonyl-(2'-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Me-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. We concluded that anandamide has little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimimetic system exerts a depressant effect in the CNS.



The identification of the major active constituent of Cannabis sativa, THC, by Gaoni and Mechoulam in 1964, followed by the characterization of the cannabinoid receptor (Howlett et al., 1988; Devane et al., 1988; Matsuda et al., 1990), provided a solid foundation and opened new perspectives for the study of this neurochemical system. Additionally, the isolation of an endogenous ligand designated anandamide (Devane et al., 1992), descriptions of its synthetic and metabolic pathways (Deutsch and Chin, 1993; Devane and Axelrod, 1994) and subsequent synthesis of a competitive antagonist, SR 141716A (Rinaldi-Carmona et al., 1994), furnished compelling evidence for the existence of an endocannabinergic system.



Anandamide and THC have pharmacological properties in common (see review by Di Marzo and De Petrocellis, 1997). For example, both substances produced hypomotility, hypothermia, antinociception and catalepsy in rodents. Based on the results of studies on chemical structure and biological activity, Martin et al. (1987) showed that THC derivatives



Received for publication December 26, 1997.



1 This work was supported by NIDA contract 3-8200 and grant DA 09789.



that were active on this tetrad of tests were likely to be psychoactive cannabinoids. Anandamide also produced inhibitory effects on memory (Lichtman et al., 1995), inhibited forskolin-stimulated adenylyl cyclase activity (Felder et al., 1993) and prolactin release (Romero et al., 1994) and stimulated adrenocorticotropic hormone discharge (Weidenfeld et al., 1994). Regulatory effects on dopamine (Schlicker et al., 1996) and GABA neurotransmission (Romero et al., 1995), as well as similar effects on reproductive function (Schuel et al., 1994) and the immune system (Schwarz et al., 1994), were reported.



In terms of the pharmacological determinants of dependence, there is evidence that THC causes tolerance and physical dependence in humans and animals (see reviews by Altman et al., 1996; Pertwee, 1991; Jones and Benowitz, 1976; and studies by de Fonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995). Other investigators demonstrated cross-tolerance among THC, anandamide and other cannabimimetics for their inhibitory effects on the twitch response in the vas deferens but not for their hypothermic effects (Pertwee et al., 1993).



The present study was designed primarily to address the



ABBREVIATIONS: SR 141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl; THC, O9-tetrahydrocannabinol; 2-Me-F-AN, 2-methylarachidonyl-(2'-fluoroethyl)-amide; ANOVA, analysis of variance.



598

Cannabis: The Brain's Other Supplier.

by Rosie Mestel

New Scientist 31 July 1993

Three years ago, Israeli archaeologists stumbled upon a 1600-year-old tragedy: the remains of a narrow-hipped teenage girl with the skeleton of a full-term fetus still cradled in her abdomen. With her were grey ashes that contained traces of tetra-hydrocannabinol, the active ingredient of marijuana. Could it be that the midwife had administered the plant in a last-ditch effort to bring on labour or to ease her pain?



Today, in nearby Jerusalem, another chemical is in the news -- this one extracted not from ancient ashes but from fresh, pulverised pig brain. It is anadamide, a newly christened chemical that might do naturally in our heads what marijuana does when we choose to smoke it. Anandamide's discovery, along with that of the molecule it binds to in the brain, has marijuana researchers buzzing with the best high they have had in years. The findings provide new hope for therapies that draw on the weed's long list of anecdotal medical uses: as a painkiller, appetite stimulant or nausea suppressant, to name a few. They also throw open windows onto the mysterious workings of our brains.



More recently came other exciting finds: in 1988, Allyn Howlett of St Louis University Medical School discovered a specific protein receptor for THC in mouse nerve cells -- a protein that only THC and its relatives dock onto. Two years later, Tom Bonner's group at the National Institute of Mental Health pinpointed the DNA that encodes the same receptor in rats. It is now known that humans have the receptor, too.



Finding a cannabinoid receptor implies that THC -- unlike alcohol -- has a quite precise modus operandi that taps into a specific brain function. Presumably the drug binds to nerves that have the receptor, and the nerves respond in turn by altering their behaviour. The classic effects of marijuana smoking are the consequences: changes in mood, memory, appetite, movement and perception, including pain. Researchers think THC affects so many mental processes because receptors are found in many brain regions, especially in those that perform tasks known to be disturbed during THC intoxication: in the banana-shaped hippocampus, crucial for proper memory; in the crumpled cerebral cortex, home of higher thinking; and in the primitive basal ganglion, controller of movement.



Once a specially tailored receptor was found, the next step was simple -- in theory, anyway. "The receptor had to be there for a purpose -- presumably it didn't evolve so that people could smoke cannabis and get high," says Roger Pertwee, a pharmacologist at Aberdeen University. Instead, there had to be a natural chemical inside of us that fitted onto the receptor and sent some biochemical signal cascading through the nerve cell to do who knows what. But plucking that one chemical out of a brain stuffed with millions of others was never going to be easy.



Several laboratories set to work on the problem and, fittingly, Mechoulam's was the first to come up with an answer, in the form of a greasy, hairpin-shaped chemical. The researchers dubbed it anandamide, from "ananda", the Sanskrit word for bliss. "The guy discovers the active ingredient of marijuana back in the 1960s, and now, almost 30 years later to the day, he discovers anandamide," says Paul Consroe, a neuropharmacologist at the University of Arizona. "Isn't that great?"



Mechoulam's strategy was to chase after chemicals that, like THC, are soluble in fat. By teasing these substances away from those that are water soluble, his group extracted a substance from pig brain that did indeed bind to the cannabinoid receptor. But did it act like THC? To find out they sent their specimen to Pertwee who had devised a sensitive test for cannabinoids that involved monitoring a substance's ability to stop muscle-twitching in mouse tissue, when dropped on certain nerves. "When it arrived, there was so little of it in the phial I couldn't even see it," Pertwee recalls. "We didn't know what it was - just that it was a greasy substance." But the tests went well: anandamide depressed the twitch just like THC, and last December the researchers published their results in "Science".



The mouse result gave Mechoulam and his group the encouragement they needed to extract more anandamide from pig brains and then analyse and synthesis the chemical in the lab. They also wanted more evidence that anandamide docked specifically onto the cannabinoid receptor and acted like THC, which has a very different molecular structure. And so, with Zvi Vogel and colleagues at the Weizmann Institute near Tel Aviv, they came up with a plan. They would add the DNA encoding the cannabinoid receptor to hamster or monkey cells growing in dishes. The cells equipped with this DNA would then produce masses of receptor, which would sit in the cell membrane ready and available for any chemical "key" that should happen along. Vogel's researchers would add anandamide to the cells and watch what happened.



The results, published in July's issue of the "Journal of Neurochemistry," were clear: anandamide acted as a key, and a precise one at that, sticking only to the cells containing the receptor, and not to others. What's more, when anandamide stuck to the cells, it triggered biochemical changes similar to those associated with THC and related chemicals. Not only did anandamide fit the same lock as THC, but it appeared to open similar doors in the brain.



More tests followed in a number of laboratories, and those researchers found that in every way that has been tested so far, anandamide acts very much like THC. But why would we want such a mind-altering substance in our brains?



Studies on another class of drugs provide a useful parallel. Opiates such as morphine and heroin act upon the body's nervous system to cause euphoria and block pain. In 1973, natural opioids, which behave in the same way as opiates, but have a different structure, were pulled out of the body. It appears that when the body is under serious assault, nerve cells spit out these opioids, which promptly bind to other nerve cells to stop pain signals dead in their tracks. At the same time, they fasten onto sites in the brain to induce a feeling of wellbeing.



Anandamide, like the natural opioids, will probably have its own specific set of jobs to perform in the brain and body. The effects of THC give a rough guide to what these might be: involvement in mood, memory and pain are obvious examples.



But what would the brain be like without anandamide? Researchers intend to find out. Bonner is gearing up to produce a genetically engineered mouse that has no cannabinoid receptors: no receptors, no anandamide function. Others want to tinker with anandamide to make a version that binds to the receptor but doesn't trigger any change in the nerve's behaviour. Added to a mouse, it would stop the body's real, internal anandamide from doing its job. Researchers are also excited by anandamide's possible role in mental and neurological disease. There are also other questions to be asked. If anandamide, like THC, hampers memory, could a drug with the opposite effects -- a "memory pill" -- be made? "It's all speculation for now," says Steven Childers, a pharmacologist at Bowman Gray School of Medicine, North Carolina, "but we like to think about these things."



It will take more time before anandamide is firmly established as the bona fide partner to the cannabinoid receptor. Meanwhile, Mechoulam's lab has two other anandamide-like chemicals waiting in the wings. And in the US, Howlett and Childers both have chemicals of an entirely different kind that bind to the receptor: they are water soluble, not fat soluble. The importance of each remains to be seen.



Whatever anandamide turns out to be, it provides pharmacologists with a fresh plan of attack in their hunt for drugs that act like the cannabinoids. Such drugs could be valuable to help keep at bay the nausea of cancer chemotherapy; to stimulate appetite in AIDS patients; to dampen tremors in neurological disorders; to reduce eye pressure in patients with glaucoma; and to dull pain in those for whom other painkillers do not work.



Cannabinoids can do at least some of these things, with one small drawback [sic.]: they also make the recipient high. The holy grail of cannabinoid therapeutics has been to separate what causes the high from the source of the desired effects, by chemical tinkering with THC or its relations -- shortening a side group on one part of the molecule, lengthening a carbon chain in another -- in the hope that the "undesirable" effects will be lost in the reshuffle. Despite the drug's dubious reputation, several US pharmaceuticals spent several years trying to make this work, but without success. Nor did they reach another equally sought after goal: an antagonist that will block the effects of THC and similar substances when taken.



Until marijuana researchers succeed in doing something along these lines, it is unlikely that drugs companies will pay much attention. "There is a real stigma with working with drugs of abuse," says Billy Martin, a pharmacologist at the Medical College of Virginia. "If drugs companies had three choices of classes of drugs to work on and one was a drug of abuse, they're just not going to work on the drug of abuse." This view is shared by Larry Melvin, who worked on the Pfizer pharmaceuticals company's now defunct cannabinoid therapeutics programme. "What will ultimately legitimise the field in a big way is if researchers can come up with a really good therapeutic ability. Then you'll see the companies turn around."



But Gabriel Nahas, an anaesthetist from Columbia University in New York, who has spoken out against marijuana use for many years, maintains that THC's effects on the brain are too general and too toxic for this route ever to work. The discovery of anandamide and its receptor have not changed his mind. "The brain is a computer," he says. "To put THC in the brain is akin to putting a bug in the computer. I'm sticking to my guns about its harmful effects -- not only to man but to society."



Only time will reveal the value of anandamide and its receptor to drug therapy. But the importance of these discoveries to brain research is not in doubt. "We're no longer just dealing with the pharmacology of a recreational drug," says Pertwee. "We're dealing with the physiology of a newly discovered system in the brain. And that's an enormously bigger field."



source: http://nepenthes.lyc...anandamide.html

<strong>Anandamides & Glaucoma, David Pate, PhD, MSc
</strong>



http://www.youtube.com/watch?v=aBCDZ-czKuM











Addressing 2002 Clinical Cannabis Therapeutics Conference in Portland, OR, Dr. Pate demonstrates that Anandamide, the "Bliss Molecule" naturally occuring in the body, has potential as an isolated compound to lower inter-ocular pressures. Also, Anandamide has neuronal protection properties: 1. NMDA hyper-excitability blockade 2. Microcirculatory stimulation 3. Apoptosis suppression 4. Free-Radical scavenging 5. TNF - alpha inhibition http://video.google....160958789588720

[EDDIEKIRK]

Cannabis: Professor Raphael Mechoulam - Discovery of THC in 1964, Anandamide in 1992



Raphael Mechoulam is an Israeli professor for Medicinal Chemistry and Natural Products at the Hebrew University of Jerusalem. While working on research at the Weizmann Institute of Science in 1964, Michoulam succeeded in the isolation, structure elucidation and total synthesis of delta9-tetrahydrocannabinol, the main active principle of cannabis.





This video discusses what THC does to the brain, it also touches on the 1992 discovery of Anandamide, also known as N-arachidonoylethanolamine or AEA, which is an endogenous cannabinoid neurotransmitter found in human organs. When the compound is released into the brain it affects memory, appetite and pain. It was isolated and its structure was first described in 1992.





Over the past few years, Professor Mechoulam, has become a great inspiration to activists, doctors, scientists and citizens worldwide for his dedication and continual striving to find cures to devastating human ailments, such as P.T.S.D. and chronic pain.





Source: Botany of Desire

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[EDDIEKIRK]

One of many Cures for cancer under a direct attack by 100% criminal and corrupted FDA and US Government !! - Very effective natural Cure, combined though with Cannabis Flower Extract would make it perfect and raise the success rate from ca. 40 to 95% for patients that had not gone under Chemo and radiation and for those that did it would still raise the success rate from 25 to ca 70% - I like to combine things, as you can with Natural medicines as mush as you want, like Colloidal Silver and Gold for Inflammations, Infections, viruses and bacteria's, Cannabis for setting all bodily functions and Systems in balance and it has several Cancer fighting properties of its own, Laetrile an other effective Cancer fighter, Ozone and active H for higher Oxygen levels in the blood, Becks Protocol for cleaning the blood from parasites and higher the Oxygen intake of the read blood-cells, change Diet, quit Sugar and Aspartame, Drink Clean water and good humor - All of these methods are Banned by FDA and All of these methods have only one "Side-effect": Perfect Health.





Dr. Burzynski discovery of antineonplastons is revolutionizing addition to the natural pharmacology and his relentless Fight with FDA for decades is more than remarkable and inspiring for all of us fighting for free Natural treatments, but alone not as effective as it could be.. - This is a MUST SEE documentary for all who work for Free Natural medicine, life liberty and justice -





~ OneLove ~ JBB





<strong>CANCER CURE - Watch NOW
</strong>

http://www.youtube.com/watch?v=HrJ1B46q7PE

[EDDIEKIRK]

Thanks for watching this very touching story. Why do we put our children through so much? Because we love them.. Please everyone with a sick child, listen to all your instincts, read as much as you can. Ask as many questions as you can think, of.



God Bless you all.

One Love

EK